This invention relates to microfluidics and laboratory automation.
The development of automated combinatorial chemistry systems and ultra-high throughput screening systems have dramatically increased the number of compounds per unit time being synthesized and screened in drug discovery programs. Such technology involves rapid handling of large numbers of very small samples. For example, thousands of new compounds per week may be produced, with each compound being concentrated in a total volume of only 50 microliters. Microliter amounts of sample often must suffice for hundreds of screening assays. Conventionally, aliquots of the concentrated, liquid sample are dispensed using xe2x80x9csip and spitxe2x80x9d liquid handling technology, diluted in an appropriate medium, and re-dispensed into an assay mixture, again using sip and spit technology. This xe2x80x9creformattingxe2x80x9d process adds complexity to the overall process, thereby increasing time and cost per assay. In addition, reformatting generates waste of valuable sample material.
The invention features a method of packaging a multiplicity of liquids for shipment, storage and metered dispensing. The method includes: (a) providing an integrated array of isolated reservoir units alignable with an array of liquid-receiving units (LRUs); (b) dispensing the liquids into the array of reservoir units; and (c) incorporating a dispensing tap into each reservoir unit to form a reservoir/tap unit sealed against spillage or leakage of the liquids. Preferably, the reservoir units are also sealed against air and light. The array of LRUs can be a multiwell container such as a 96-well microtiter plate, a 384-well microtiter plate, or a 1536-well microtiter plate. In preferred embodiments, each tap includes a translatable metering tube, which contains a tube end closure, a port, and a translatable piston. In some embodiments, the liquid is a solution of one or more chemical compounds. In some embodiments, liquid-contacting surfaces of the reservoir and tap are resistant to damage by acids, bases, salts and organic solvents.
The invention also features a method for independently dispensing a metered amount of a plurality of liquids into an array of LRUs. The method includes: (a) providing an array of isolated, sealed, tapped reservoir units, the array of reservoir units including a reservoir for each LRU, each reservoir unit containing an integrated metering tap; (b) aligning the array of reservoir/tap units with the array of LRUs so that each tap is aligned with one LRU; and (c) actuating one or more taps in the array of reservoir units so that each actuated tap dispenses a metered amount of liquid into the LRU aligned with that tap. The metered amount dispensed into any particular unit in the array can be from zero nanoliters to 20 microliters, preferably from 20 nanoliters to 2 microliters, e.g., 50 nanoliters to 500 nanoliters.
Preferably no tap contacts an LRU surface, and the liquid dispensed from each tap breaks contact with the tap before contacting the LRU aligned with that tap or the contents of an LRU. Preferably, the reservoirs are sealed against air and light. The array of reservoir units can be aligned directly above the array of LRUs. In some embodiments, each tap can be actuated independently. Preferably, each tap contains minimal (or substantially zero) dead volume. Examples of suitable LRUs are multi-well containers such as a 96-well microtiter plate, a 384-well microliter plate and a 1536-well microtiter plate.
In some embodiments of the dispensing method, each tap includes a translatable metering tube, which can contain a tube end closure, a port and a translatable piston. Actuating the tap can include translating the tube so that the port is inside the reservoir; drawing liquid from the reservoir through the port and into the tube; translating the tube so that the port is outside the reservoir; and expelling liquid from the tube through the port and into a fluid output channel. The liquid can be drawn into the tube and expelled from the tube by translating the piston. Some embodiments include propelling the expelled liquid away from the port. Propelling the expelled liquid can be achieved by applying a propelling fluid to the expelled liquid. The propelling fluid can be a propelling liquid, e.g., an aqueous liquid or an organic solvent; or a propelling gas, e.g., air, nitrogen or argon. Some embodiments of the method include providing a curtain of forced gas surrounding the fluid output tip, with the forced gas moving in the same direction as the liquid exiting from the fluid output tip.
The invention also features devices for storing, shipping and dispensing metered, nanoliter or microliter amounts of liquid into a liquid receiving unit.
An offset nozzle-type device includes: an array of isolated, sealed, reservoir/tap units, each unit containing an integrated metering tap, each tap including: (a) a metering tube translatable between a fill position inside the reservoir and an expel position outside the reservoir. The metering tube includes (1) a tube end closure, e.g., a plug, in a lower portion of the tube, (2) a port above the tube end closure, and (3) a piston in an upper portion of the tube. The piston is movable between a down position that seals the port and an up position above the port; and (b) a fluid output channel having an upper portion in fluid communication with the port when the tube is in the expel position and a lower portion terminating in a fluid output tip. A compressed gas path in fluid communication with the fluid output channel at a point upstream of the port when the tube is in the expel position can be used to apply a gas stream to propel the expelled liquid through the fluid output channel. Some embodiments include a compressed gas path terminating in an annular opening surrounding the fluid output tip.
An in-line nozzle embodiment of the device includes an array of isolated, sealed reservoir/tap units, each unit containing an integrated metering tap, each tap including: (a) a metering tube translatable between a fill position inside the reservoir and an expel position outside the reservoir. The metering tube contains (1) a tube end closure in a lower portion of the tube, (2) a port above the tube end closure, and (3) a piston in an upper portion of the tube. The piston is movable between a down position that seals the port and an up position above the port; and (b) a nozzle containing a fluid output channel through which the tube extends when in the down position, the fluid output channel having an upper end in fluid communication with a compressed gas path, and a lower end terminating in a nozzle tip.
A nozzleless-type device includes an array of isolated, sealed reservoir/tap units, each unit containing an integrated metering tap. Each metering tap including a metering tube translatable between a fill position inside the reservoir and an expel position outside the reservoir. The metering tube contains (1) a tube end closure in a lower portion of the tube, (2) a port above the tube end closure, and (3) a piston in an upper portion of the tube. The piston is movable between a down position that seals the port and an up position above the port. Each unit contains a compressed gas path, which includes one or more compressed gas outlets located above the port so that it can deliver a downward gas stream across the port, when the metering tube is in the expel position.
In each of the above devices, movement of the piston from the up position to the down position can displace, for example, 10 nanoliters to 20 microliters, preferably from 20 nanoliters to 2 microliters, e.g., 50 nanoliters to 500 nanoliters. The array of reservoir units can be arranged so that each tap aligns with one well of a multi-well container such as a 96-well microtiter plate, a 384-well microtiter plate or a 1536-well microtiter plate. However, with suitable equipment, any particular tap can be positioned to dispense into any chosen well.
As used herein, xe2x80x9cliquid-receiving unitxe2x80x9d (LRU) means: (a) a defined or addressable area on a flat liquid-receiving surface, e.g., a glass slide; (b) a depression or well in a liquid-receiving container, e.g., a microtiter plate, or (c) a receptacle, e.g., a test tube, vial or bottle.
As used herein, xe2x80x9creservoir/tap unitxe2x80x9d means a single tapped reservoir.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.